Herb-Drug Interactions: Liquorice

2011

Qycyrrhiza glabra L. (Fabaceae)

Synonym(s) and related species

Licorice.

Spanish and Italian liquorice is Glycyrrhiza glabra var typica Reg. et Herd.

Persian or Turkish liquorice is Glycyrrhiza glabra L var violacea Boiss.

Russian liquorice is Glycyrrhiza glabra L var glanduli-fera.

Chinese liquorice is the closely related Glycyrrhiza uralensis Fisch., also known as Gancao.

Pharmacopoeias

Licorice (US Ph 32); Liquorice (British Ph 2009); Liquorice Dry Extract for Flavouring Purposes (British Ph 2009); Liquorice Liquid Extract (British Ph 2009); Liquorice Root (European Ph 2008); Liquorice Root for use in THM (British Ph 2009); Powdered Licorice (US Ph 32); Powdered Licorice Extract (US Ph 32); Processed Liquorice Root for use in THMP (British Ph 2009); Standardised Liquorice Ethanolic Liquid Extract (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

Liquorice has a great number of active compounds of different classes that act in different ways. The most important constituents are usually considered to be the oleanane-type triterpenes, mainly glycyrrhizin (glycyrrhizic or glycyrrhizinic acid), to which it is usually standardised, and its aglycone glycyrrhetinic acid. There are also numerous phenolics and flavonoids of the chalcone and isoflavone type, and many natural coumarins such as liqcoumarin, umbelliferone, glabrocoumarones A and B, herniarin and glycyrin. It also contains polysaccharides such as glycyrrhizan GA, and a small amount of volatile oil.

Use and indications

The dried root and stolons of liquorice are used as an expectorant, antispasmodic and anti-inflammatory, and to treat peptic and duodenal ulcers. Liquorice is widely used in traditional oriental systems of medicine, and as a flavouring ingredient in food. It has mineralocorticoid and oestrogenic activity in large doses, as a result of glycyrrhetinic acid, and has many other reputed pharmacological effects.

Pharmacokinetics

Prolonged intake of high doses of liquorice extract, or its constituent glycyrrhizin, on probe cytochrome P450 isoenzyme substrates was investigated in mice. With repeated treatment, both liquorice extract and glycyrrhizin significantly induced hepatic CYP3A and to a lesser extent, CYP1A2.

In a single-dose study in 2 healthy subjects, plasma levels of glycyrrhetic acid were much lower after administration of aqueous liquorice root extract 21 g (containing 1600mg glycyrrhizin) than after the same 1600-mg dose of pure glycyrrhizin. This suggests that the biological activity of a given dose of glycyrrhizin might be greater if taken as the pure form than as liquorice. This confirmed data from a study in rats. Note that much of the evidence relating to possible interactions is for pure constituents. These findings therefore suggest that the effect of liquorice might be less than that of pure glycyrrhizin at the same dose.

Interactions overview

Liquorice appears to diminish the effects of antihypertensives and may have additive effects on potassium depletion if given in large quantities with laxatives and corticosteroids. Iron absorption may be decreased by liquorice, whereas antibacterials may diminish the effects of liquorice. A case report describes raised digoxin levels and toxicity in a patient taking liquorice. Although it has been suggested that liquorice may enhance the effects of warfarin, there appears to be no evidence to support this. Note that liquorice is a constituent of a number of Chinese herbal medicines. See under bupleurum9, for possible interactions of liquorice given as part of these preparations.

Liquorice + Antihypertensives

Liquorice may cause fluid retention and therefore reduce the effects of antihypertensives. Additive hypokalaemia may also occur with loop and thiazide diuretics.

Clinical evidence

In 11 patients with treated hypertension, liquorice 100 g daily for 4 weeks (equivalent to glycyrrhetinic acid 150 mg daily) increased mean blood pressure by 15.3/9.3 mmHg. Smaller rises (3.5/ 3.6mmHg) were seen in 25 normotensive subjects taking the same dose of liquorice. In another study in healthy subjects liquorice 50 to 200 mg daily for 2 to 4 weeks (equivalent to glycyrrhetinic acid 75 to 540 mg daily) increased systolic blood pressure by 3.1 to 14.4 mmHg. The group taking the largest quantity of liquorice experienced the greatest rise in systolic blood pressure, and was the only group to have a statistically significant rise in diastolic blood pressure.

There are many published case reports of serious hypertension occurring in people consuming, often, but not always, excessive doses of liquorice from various sources (confectionery, alcoholic drinks, flavoured chewing tobacco, herbal teas, herbal medicines).

Experimental evidence

Because of the quality of the clinical evidence, experimental data have not been cited. There is an extensive literature, which has been the subject of a review.

Mechanism

Ingestion of liquorice inhibits 11 P-hydroxysteroid dehydrogenase type 2, thereby preventing the inactivation of cortisol to cortisone.This results in mineralocorticoid effects including sodium and water retention (leading to hypertension) and hypokalaemia. This effect would oppose the effects of drugs used to lower blood pressure. In addition, the potassium-depleting effect of liquorice would be expected to be additive with loop and thiazide diuretics. The mineralocorticoid effect of liquorice is due to the content of glycyrrhetinic acid (a metabolite of glycyrrhizic acid), and therefore deglycyrrhizinated liquorice would not have this effect.

Importance and management

The ability of liquorice to increase blood pressure is well established. The dose required to produce this effect might vary between individuals, and the evidence from the study cited suggests that patients with hypertension might be more sensitive to its effect. It is probably not appropriate for patients taking antihypertensive drugs to be treated with liquorice, especially if their hypertension is not well controlled. Although liquorice-containing confectionary and other foodstuffs have also been implicated in this interaction it is usually when it has been consumed to excess. It seems unlikely that the occasional consumption of small amounts of these products will cause a notable effect. Nevertheless, in patients with poorly controlled blood pressure it may be prudent to ask about liquorice consumption to establish whether this could be a factor.

Note also that the potassium-depleting effect of liquorice would be additive with that of potassium-depleting diuretics such as loop diuretics and thiazides. Deglycyrrhizinated liquorice would not be expected to have these effects.

Liquorice + Caffeine

For mention that sho-saiko-to (of which liquorice is one of 7 constituents) only slightly reduced the metabolism of caffeine in one study, see Bupleurum + Caffeine.

Liquorice + Carbamazepine

For mention that sho-saiko-to (of which liquorice is one of 7 constituents) did not affect the metabolism of carbamazepine in an animal study, see Bupleurum + Carbamazepine.

Liquorice + Corticosteroids

Liquorice, if given in large quantities with corticosteroids, may cause additive hypokalaemia.

Clinical evidence

(a) Dexamethasone

In a parallel group study, 6 patients were given glycyrrhizin 225 mg daily for 7 days, and 6 patients were given the same dose of glycyrrhizin and dexamethasone 1.5 mg daily for 7 days. The mineralocorticoid effects of glycyrrhizin were significantly reduced by dexamethasone; cortisol plasma concentrations and urinary excretions were reduced by up to 70%.

(b) Hydrocortisone

Glycyrrhizin slightly increased the AUC of cortisol by 13.6% in 4 patients with adrenocorticol insufficiency taking oral hydrocortisone 20 to 40 mg daily. Note that glycyrrhizin had no effect on endogenous cortisol levels in 7 control subjects without adrenal insufficiency.

In a study in 23 healthy subjects, topical glycyrrhetinic acid markedly potentiated the activity of topical hydrocortisone, as assessed by cutaneous vasoconstrictor effect.

(c) Prednisolone

A study in 6 healthy subjects found that, after taking four 50-mg oral doses of glycyrrhizin at 8-hourly intervals, followed by a bolus injection of prednisolone hemisuccinate 96 micrograms/kg, the AUC of total prednisolone was increased by 50% and the AUC of free prednisolone was increased by 55%. This confirms previous findings in which the glycyrrhizin 200 mg was given by intravenous infusion.

Glycyrrhizin slightly increased the AUC of prednisolone by about 16 to 20% in 12 patients who had been taking oral prednisolone 10 to 30 mg daily for at least 3 months.

Experimental evidence

Several experimental studies have found that glycyrrhizin and glycyrrhetinic acid (from liquorice) inhibit the conversion of cortisol to the inactive steroid cortisone by 11 P-hydroxysteroid dehydrogenase, thereby having mineralocorticoid effects.

In vitro, glycyrrhetinic acid (the aglycone of glycyrrhizin), inhibited 20-hydroxysteroid dehydrogenase, which reduced the conversion of prednisolone to its metabolite 20-dihydropred-nisolone.

Mechanism

Inhibition of 11 P-hydroxy steroid dehydrogenase by glycyrrhetinic acid may slightly delay the clearance of hydrocortisone and prednisolone and thereby enhance their effects. However, note that whether a mineralocorticoid or glucocorticoid is a substrate for this enzyme system depends on its chemical structure. Therefore, it cannot be assumed that liquorice will inhibit the inactivation of all cortico steroids.

Dexamethasone appears to attenuate the mineralocorticoid effects of glycyrrhizin because it suppresses endogenous cortisol secretion (causes adrenal suppression). Other corticosteroids would be expected to interact similarly if given in adrenal-suppressant doses.

Deglycyrrhizinated liquorice would not have these effects.

Importance and management

The clinical importance of these observations is uncertain. Doses of corticosteroids sufficient to cause adrenal suppression would be expected to reduce the mineralocorticoid activity of liquorice, but mineralocorticoid activity might still occur. Glycyrrhizin (an active constituent of liquorice) and its metabolite glycyrrhetinic acid slightly increased the plasma levels of hydrocortisone and prednisolone and markedly potentiated the cutaneous effects of hydrocortisone. This suggests that liquorice will slightly potentiate the effects of these steroids. However, this might not apply to other corticosteroids (see Mechanism, above). Nevertheless, it might be prudent to monitor the concurrent use of liquorice and corticosteroids, especially if liquorice ingestion is prolonged or if large doses are taken, as additive effects on water and sodium retention and potassium depletion may occur.

Liquorice + Digitalis glycosides

An isolated case of digoxin toxicity has been reported in an elderly patient attributed to the use of a herbal laxative containing kanzo (liquorice).

Clinical evidence

An 84-year-old man taking digoxin 125 micrograms daily and furosemide 80 mg daily complained of loss of appetite, fatigue and oedema of the lower extremities 5 days after starting to take a Chinese herbal laxative containing liquorice (kanzo) 400 mg and rhubarb (daio) 1.6 g three times daily. He was found to have a raised digoxin level of 2.9nanograms/mL (previous level 1 nanogram/mL) with a pulse rate of 30bpm, and a slightly low potassium level (2.9mmol/L).

Experimental evidence

No relevant data found.

Mechanism

The reason for the increase in digoxin levels is unclear. Digoxin inhibits the sodium-potassium ATPase pump, which is concerned with the transport of sodium and potassium ions across the membranes of the myocardial cells. Potassium loss caused by a combination of the liquorice, rhubarb and diuretics exacerbated the potassium loss from the myocardial cells, thereby enhancing the bradycardia, already caused by an elevated digoxin level. Hypokalaemia also promotes the binding of digoxin to myocardial cells. The patient’s pre-existing cardiovascular disease may have also predisposed the patient to enhanced digoxin effects.

Importance and management

Evidence appears to be limited to one case. It is likely that the effects of the elevated digoxin levels were exacerbated by the hypokalaemia possibly caused by the herbal laxative. The theoretical basis for an interaction between liquorice and digoxin is well established, but there are few actual cases. Any herbal preparation that can reduce potassium levels would be expected to increase the risk of digoxin toxicity. This is likely to be additive with other concurrent medications that a patient may also be taking that can cause hypokalaemia, such as loop diuretics. It would be prudent to exercise caution in patients who are taking digitalis glycosides and who regularly use/abuse laxatives including liquorice and/or anthraquinone-containing substances such as rhubarb. However, note that, if these laxatives are used as recommended (at a dose producing a comfortable soft-formed motion), then this interaction is probably unlikely to be important.

Liquorice + Food

No interactions found. Note that liquorice is consumed as part of the diet.

Liquorice + Herbal medicines

See under Liquorice + Laxatives.

Liquorice + Iron compounds

The interaction between liquorice and iron compounds is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

Liquorice extract 5 g/100 mL slightly enhanced the absorption index of iron by about 44% in rats.

Mechanism

Unknown. It may be related to the content of iron and vitamin C (which promotes iron absorption) in the liquorice extract.

Importance and management

The experimental evidence suggests that liquorice might slightly enhance the bioavailability of medicinal iron, but further study is needed to assess the clinical relevance of this. At present, no action is considered necessary.

Liquorice + Laxatives

Liquorice may cause additive hypokalaemia if given in large quantities with laxatives.

Evidence and mechanism

(a) Additive potassium depletion

Liquorice root may cause water retention and potassium depletion. Chronic diarrhoea caused by the long-term use or abuse of stimulant laxatives such as aloes and senna may lead to excessive loss of water and potassium, and can also lead to potassium deficiency. Theoretically, concurrent use of these herbs might have additive effects on potassium loss. Although the increased potential for potassium deficiency on combined use is mentioned in some reviews, there appear to be few clinical reports of this having occurred. Moreover, laxatives containing both senna and liquorice are available in some countries. One report describes four cases of pseudohyperaldosteronism (hypertension, hypokalaemia and suppression of the renin-aldosterone axis) in patients taking liquorice-containing laxatives for chronic constipation. In three of the patients, the preparation had been prepared by a herbalist and the fourth patient was taking a proprietary preparation containing senna and liquorice (Midro). The liquorice doses were high, varying from 0.5 to 8 g daily. Patients had the liquorice laxative withdrawn and replaced by glycerine suppositories or lactulose, and received spironolactone 200 mg daily for 2 weeks to correct blood pressure and potassium. Two months later, the patients had no signs or symptoms of hyperaldosteronism. It is not possible to say what contribution senna made to these cases, as the effects seen could be attributed to liquorice alone. Note that a similar combination laxative of liquorice with rhubarb caused mild hypokalaemia and digoxin toxicity, see Liquorice + Digoxin.

(b) Reduced absorption of liquorice

The introduction to an animal study briefly reported that, in a study in healthy subjects, the AUC and maximum levels of glycyrrhetic acid were much lower after oral administration of Onpito, a Kampo medicine composed of five herbs including liquorice and rhubarb, than after other Kampo medicines containing liquorice and not containing rhubarb. In a series of experiments in rats, the AUC of glycyrrhetic acid, a major component of liquorice, was reduced by up to about 70% by sennoside A, an anthraquinone derivative found in rhubarb. The authors propose that competitive inhibition of the anthraquinones on glycyrrhetic acid transportation by monocarboxylic acid transporter (MCT1) and induction of P-glycoprotein in the intestinal tract may be possible mechanisms for reducing the absorption of glycyrrhetic acid.

In a study in rats, the AUC and maximum level of glycyrrhetic acid were reduced by 80% and 85% respectively, when a single dose of shaoyao-gancao-tang was given 5 hours after a single dose of sodium picosulfate. However, it was found that the reduction in glycyrrhetic acid levels seen with the laxative could be markedly attenuated by the repeated administration of shaoyao-gancao-tang.

It was suggested that sodium picosulfate could reduce the metabolism of the glycoside glycyrrhizin to its active metabolite glycyrrhetic acid. Note that shaoyao-gancao-tang is a traditional Chinese medicine containing liquorice (gancao), of which glycyrrhizin is a major constituent.

Importance and management

The possible additive potassium depletion in patients given liquorice and anthraquinone-containing laxatives (such as senna and rhubarb) is a theoretical interaction, but bear it in mind in patients who are taking liquorice and who are regular users/abusers of anthraquinone-containing substances. However, note that, if anthraquinone laxatives are used as recommended (at a dose producing a comfortable soft-formed motion), this interaction is unlikely to be important.

It is unclear if sodium picosulfate affects the efficacy of liquorice as a laxative, and combination products are common.

Liquorice + Ofloxacin

For mention that sho-saiko-to and sairei-to (of which liquorice is one of the constituents) did not affect the metabolism of ofloxacin, see Bupleurum + Ofloxacin.

Liquorice + Tolbutamide

For conflicting evidence from animal studies that sho-saiko-to (of which liquorice is one of 7 constituents) might increase or decrease the rate of absorption of tolbutamide, see Bupleurum + Tolbutamide.

Liquorice + Ulcer-healing drugs

The interaction between liquorice and ulcer-healing drugs is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, a single oral dose of shaoyao-gancao-tang was given alone and on the last day of a number of different drugs given twice daily for 7 doses. Pretreatment with amoxicillin with metronidazole or clarithromycin with metronidazole markedly reduced the AUC of glycyrrhetic acid by about 90%. Hyoscine or omeprazole had no effect on the AUC of glycyrrhetic acid. Cimetidine decreased the AUC of glycyrrhetic acid by 42%, but this was not statistically significant. However, in a further study, it was found that the reduction in glycyrrhetic acid levels seen with the antibacterials could be markedly attenuated by the repetitive administration of shaoyao-gancao-tang.

Mechanism

It was suggested that amoxicillin, clarithromycin and metronidazole decimate intestinal bacteria and so reduce the hydrolysis of the glycoside glycyrrhizin to glycyrrhetic acid, which is the form absorbed. Note that shaoyao-gancao-tang is a traditional Chinese medicine containing liquorice (gancao), of which glycyrrhizin is a major constituent.

Importance and management

There appear to be no clinical data regarding an interaction between liquorice and ulcer-healing drugs. The findings of the single-dose experimental study suggested that the clinical efficacy of shaoyao-gancao-tang in peptic ulcer disease might be reduced by the concurrent use of antibacterials used to eliminate Helicobacter pylori infection. However, the multiple-dose study suggests that, with repeated doses of the herbal medicine, the interaction might not be clinically relevant.

Liquorice + Warfarin

The interaction between liquorice and warfarin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, pretreatment with gancao aqueous extract 900 mg/kg daily by gastric lavage for 6 days reduced the AUC of a single 2-mg/kg dose of intravenous warfarin by about 38% and increased its clearance by 57%.

Mechanism

The authors of the study in rats suggest that gancao increases the metabolism of warfarin by the activation of the pregnane X receptor (PXR), which increases the expression of cytochrome P450 subfamily CYP3A, and isoenzyme CYP2C9.

Importance and management

Evidence appears to be limited to one experimental study in rats. It has been hypothesised that liquorice (gancao) might increase the effect of warfarin because of its natural coumarin content, but the coumarin constituents of liquorice are not known to be anticoagulants, and there is no evidence of liquorice acting as an anticoagulant. Furthermore, liquorice is not known as a food substance that reduces the activity of warfarin anticoagulation, nor is it known to induce the metabolism of other drugs; however, the experimental study introduces the possibility that it might. The evidence presented is too slim to make any specific recommendations regarding concurrent use.